Strong signature of natural selection within an FHIT intron implicated in prostate cancer risk

Previously, a candidate gene linkage approach on brother pairs affected with prostate cancer identified a locus of prostate cancer susceptibility at D3S1234 within the fragile histidine triad gene (FHIT), a tumor suppressor that induces apoptosis. Subsequent association tests on 16 SNPs spanning approximately 381 kb surrounding D3S1234 in Americans of European descent revealed significant evidence of association for a single SNP within intron 5 of FHIT. In the current study, resequencing and genotyping within a 28.5 kb region surrounding this SNP further delineated the association with prostate cancer risk to a 15 kb region. Multiple SNPs in sequences under evolutionary constraint within intron 5 of FHIT defined several related haplotypes with an increased risk of prostate cancer in European-Americans. Strong associations were detected for a risk haplotype defined by SNPs 138543, 142413, and 152494 in all cases (Pearson's χ2 = 12.34, df 1, P = 0.00045) and for the homozygous risk haplotype defined by SNPs 144716, 142413, and 148444 in cases that shared 2 alleles identical by descent with their affected brothers (Pearson's χ2 = 11.50, df 1, P = 0.00070). In addition to highly conserved sequences encompassing SNPs 148444 and 152413, population studies revealed strong signatures of natural selection for a 1 kb window covering the SNP 144716 in two human populations, the European American (π = 0.0072, Tajima's D= 3.31, 14 SNPs) and the Japanese (π = 0.0049, Fay & Wu's H = 8.05, 14 SNPs), as well as in chimpanzees (Fay & Wu's H = 8.62, 12 SNPs). These results strongly support the involvement of the FHIT intronic region in an increased risk of prostate cancer. © 2008 Ding et al

A Bayesian assessment of an approximate model for unconfined water flow in sloping layered porous media

The prediction of water table height in unconfined layered porous media is a difficult modelling problem that typically requires numerical simulation. This paper proposes an analytical model to approximate the exact solution based on a steady-state Dupuit–Forchheimer analysis. The key contribution in relation to a similar model in the literature relies in the ability of the proposed model to consider more than two layers with different thicknesses and slopes, so that the existing model becomes a special case of the proposed model herein. In addition, a model assessment methodology based on the Bayesian inverse problem is proposed to efficiently identify the values of the physical parameters for which the proposed model is accurate when compared against a reference model given by MODFLOW-NWT, the open-source finite-difference code by the U.S. Geological Survey. Based on numerical results for a representative case study, the ratio of vertical recharge rate to hydraulic conductivity emerges as a key parameter in terms of model accuracy so that, when appropriately bounded, both the proposed model and MODFLOW-NWT provide almost identical results

The Evolution of Mammalian Gene Families

Gene families are groups of homologous genes that are likely to have highly similar functions. Differences in family size due to lineage-specific gene duplication and gene loss may provide clues to the evolutionary forces that have shaped mammalian genomes. Here we analyze the gene families contained within the whole genomes of human, chimpanzee, mouse, rat, and dog. In total we find that more than half of the 9,990 families present in the mammalian common ancestor have either expanded or contracted along at least one lineage. Additionally, we find that a large number of families are completely lost from one or more mammalian genomes, and a similar number of gene families have arisen subsequent to the mammalian common ancestor. Along the lineage leading to modern humans we infer the gain of 689 genes and the loss of 86 genes since the split from chimpanzees, including changes likely driven by adaptive natural selection. Our results imply that humans and chimpanzees differ by at least 6% (1,418 of 22,000 genes) in their complement of genes, which stands in stark contrast to the oft-cited 1.5% difference between orthologous nucleotide sequences. This genomic “revolving door” of gene gain and loss represents a large number of genetic differences separating humans from our closest relatives

Bitter Taste Receptors Influence Glucose Homeostasis

TAS1R- and TAS2R-type taste receptors are expressed in the gustatory system, where they detect sweet- and bitter-tasting stimuli, respectively. These receptors are also expressed in subsets of cells within the mammalian gastrointestinal tract, where they mediate nutrient assimilation and endocrine responses. For example, sweeteners stimulate taste receptors on the surface of gut enteroendocrine L cells to elicit an increase in intracellular Ca2+ and secretion of the incretin hormone glucagon-like peptide-1 (GLP-1), an important modulator of insulin biosynthesis and secretion. Because of the importance of taste receptors in the regulation of food intake and the alimentary responses to chemostimuli, we hypothesized that differences in taste receptor efficacy may impact glucose homeostasis. To address this issue, we initiated a candidate gene study within the Amish Family Diabetes Study and assessed the association of taste receptor variants with indicators of glucose dysregulation, including a diagnosis of type 2 diabetes mellitus and high levels of blood glucose and insulin during an oral glucose tolerance test. We report that a TAS2R haplotype is associated with altered glucose and insulin homeostasis. We also found that one SNP within this haplotype disrupts normal responses of a single receptor, TAS2R9, to its cognate ligands ofloxacin, procainamide and pirenzapine. Together, these findings suggest that a functionally compromised TAS2R receptor negatively impacts glucose homeostasis, providing an important link between alimentary chemosensation and metabolic disease

Role of CCL3L1-CCR5 Genotypes in the Epidemic Spread of HIV-1 and Evaluation of Vaccine Efficacy

Polymorphisms in CCR5, the major coreceptor for HIV, and CCL3L1, a potent CCR5 ligand and HIV-suppressive chemokine, are determinants of HIV-AIDS susceptibility. Here, we mathematically modeled the potential impact of these genetic factors on the epidemic spread of HIV, as well as on its prevention.Ro, the basic reproductive number, is a fundamental concept in explaining the emergence and persistence of epidemics. By modeling sexual transmission among HIV+/HIV- partner pairs, we find that Ro estimates, and concordantly, the temporal and spatial patterns of HIV outgrowth are highly dependent on the infecting partners' CCL3L1-CCR5 genotype. Ro was least and highest when the infected partner possessed protective and detrimental CCL3L1-CCR5 genotypes, respectively. The modeling data indicate that in populations such as Pygmies with a high CCL3L1 gene dose and protective CCR5 genotypes, the spread of HIV might be minimal. Additionally, Pc, the critical vaccination proportion, an estimate of the fraction of the population that must be vaccinated successfully to eradicate an epidemic was <1 only when the infected partner had a protective CCL3L1-CCR5 genotype. Since in practice Pc cannot be >1, to prevent epidemic spread, population groups defined by specific CCL3L1-CCR5 genotypes might require repeated vaccination, or as our models suggest, a vaccine with an efficacy of >70%. Further, failure to account for CCL3L1-CCR5-based genetic risk might confound estimates of vaccine efficacy. For example, in a modeled trial of 500 subjects, misallocation of CCL3L1-CCR5 genotype of only 25 (5%) subjects between placebo and vaccine arms results in a relative error of approximately 12% from the true vaccine efficacy.CCL3L1-CCR5 genotypes may impact on the dynamics of the HIV epidemic and, consequently, the observed heterogeneous global distribution of HIV infection. As Ro is lowest when the infecting partner has beneficial CCL3L1-CCR5 genotypes, we infer that therapeutic vaccines directed towards reducing the infectivity of the host may play a role in halting epidemic spread. Further, CCL3L1-CCR5 genotype may provide critical guidance for optimizing the design and evaluation of HIV-1 vaccine trials and prevention programs